Indole derivative for treating overproduction of dihydrotestosterone

ABSTRACT

The present invention relates to an indole derivative represented by formula (1) or a salt thereof, and a pharmaceutical containing the derivative or the salt: ##STR1## wherein R 1  represents lower alkyl; R 2  represents hydrogen or phenyl which may be substituted by at least one lower alkyl, lower alkoxy or a halogen atom; R 3  represents hydrogen, lower alkyl, lower alkoxy, or phenylalkyloxy which may be substituted by halogen or lower alkyl; R 4  represents hydrogen, lower alkyl or lower alkoxy; R 5  represents hydrogen or lower alkyl; and n represents an integer of 1 to 5. This compound has the effects of both blocking α 1  -adrenergic receptors and inhibiting testosterone 5α-reductases, and is useful as a remedy and/or a preventive for diseases caused by dihydrotestosterone overproduction, such as prostatic hypertrophy, and diseases accompanying the same, such as urination disorder, male pattern alopecia, acne, and so forth.

This application is a 371 of PCT/JP95/00599 filed Mar. 29, 1995.

TECHNICAL FIELD

The present invention relates to novel indole derivatives which havetestosterone 5α-reductase inhibitory action and thus are effective inthe treatment and/or prevention of diseases caused by overproduction ofdihydrotestosterone, e.g., prostatic hypertrophy or accompanyingurination disorder, male pattern alopecia, and acne; and which have α₁-adrenergic receptor blocking action and thus are capable of selectivelycuring disorders regarding passage through the bladder neck to therebyimprove urination disorder.

BACKGROUND ART

Testosterone 5α-reductase is an enzyme that reduces testosterone, a malehormone (androgen), into dihydrotestosterone. The produceddihydrotestosterone has been elucidated to play an important role in themechanism of the generation and progress of prostatic hypertrophy, malepattern alopecia, and acne (J. Steroid Biochemistry, 11, 609 (1979), J.Clinical Endocrinol and Metabolism, 56, 139 (1983), and Japanese PatentApplication Laid-Open (kokai ) No. 1-139558). Indoles are known ascompounds that exhibit testosterone 5α-reductase inhibitory activities,(Japanese Patent Application Laid-Open (kokai) No. 4-244061,WO93/02050).

α-Adrenergic receptors are known to participate in contraction of smoothmuscles. Particularly, recent research has revealed that α₁ -adrenergicreceptors strongly participate in contraction of the sphincter in thehuman bladder neck (J. Urol., 134, 396 (1985)). Therefore, blockers ofthe receptors are considered to serve as drugs that are capable ofselectively treating urination disorders and frequent urinationaccompanied by prostatic hypertrophy. As compounds that have a blockingaction against such α₁ -adrenergic receptors, there are known piperazinederivatives (WO89/12634, WO90/03972).

Disurea, which aged people frequently suffer, is caused by constrictionof urethra due to the tonus of sympathetic nerves present in the bladderneck or by urinary obstruction associated with prostatic hypertrophy,and makes urination difficult. In recent years, disurea has been treatedby the combined use of an α₁ -adrenergic receptor blocking agent and anantiandrogenic agent. However, this is not satisfactory in view of thedrug administration schedule.

Therefore, it is desired to develop drugs having both benefits ofsymptomatic therapy, which exerts immediate effects as exerted by α₁-adrenergic receptors, and of radical therapy, which exhibits its effectslowly but radically, as in the case of testosterone 5α-reductaseinhibitors. However, compounds having both α₁ -adrenergic receptorblocking action and testosterone 5α-reductase inhibitory action have sofar not been known.

DISCLOSURE OF THE INVENTION

The present inventors conducted careful studies toward solving the aboveproblems, and surprisingly found that the indole derivatives (1)described below possess strong actions of both blocking α₁ -adrenergicreceptors and inhibiting testosterone 5α-reductases, and thus are usefulfor the treatment of prostatic hypertrophy and disorders accompanyingthe same, such as urination disorder, alopecia, and acne. The presentinvention was accomplished based on this finding.

Accordingly, the present invention provides an indole derivativerepresented by the following formula (1) or a salt thereof: ##STR2##wherein R¹ represents lower alkyl; R² represents hydrogen or phenylwhich may be substituted by at least one lower alkyl, lower alkoxy or ahalogen atom; R³ represents hydrogen, lower alkyl, lower alkoxy, orphenylalkyloxy which may be substituted by halogen or lower alkyl; R⁴represents hydrogen, lower alkyl or lower alkoxy; R⁵ represents hydrogenor lower alkyl; and n represents an integer of 1 to 5.

The present invention also provides an α₁ -adrenergic receptor blockerand testosterone 5α-reductase inhibitor comprising as an effectiveingredient the indole derivative (1) or a salt thereof.

The present invention also provides a remedy and/or a preventive forprostatic hypertrophy and disorders accompanying the same, such asurination disorder, alopecia, and acne, which comprises as an effectiveingredient the indole derivative (1) or a salt thereof.

The present invention further provides a medicine comprising the indolederivative (1) or a salt thereof as well as a carrier for medicines.

The present invention further provides use of the indole derivative (1)or a salt thereof as a medicine.

The present invention still further provides a method for the preventionor treatment of prostatic hypertrophy and disorders accompanying thesame, such as urination disorder, alopecia, and acne, characterized byadministering an effective amount of the indole derivative (1) or a saltthereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the term "lower" refers to a C1-C6 linear orbranched carbon chain, unless otherwise provided.

Accordingly, "lower alkyl groups" include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl,n-pentyl, Isopentyl, neopentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl,1-ethylpropyl, 1,2-dimethylpropyl, and hexyl.

Also, "lower alkoxy groups" include, but are not limited to, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy,n-pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, 1-methylbutoxy,2-methylbutoxy, 1-ethyipropoxy, 1,2-dimethylpropoxy, and hexyloxy.

"Halogen atoms" include fluorine, chlorine, bromine, and iodine.

In formula (1), lower alkyl groups represented by R¹, R³, R⁴, and R⁵ areC1-C6 linear or branched alkyl groups, of which C1-C4 linear or branchedalkyl groups are preferred. Particularly, methyl, ethyl, n-propyl,isopropyl, and n-butyl are preferred. Examples of preferred phenylgroups represented by R² which may be substituted by at least one loweralkyl, lower alkoxy, or a halogen atom include phenyl, C1-C4alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, andhalogen-substituted phenyl. Particularly preferred are phenyl,methylphenyl, ethylphenyl, n-propylphenyl, isopropylphenyl,isobutylphenyl, methoxyphenyl, ethoxyphenyl, chlorophenyl, bromophenyl,and fluorophenyl. Lower alkoxy groups represented by R³ or R⁴ are C1-C6linear or branched alkoxy groups, of which C1-C4 linear or branchedalkoxy groups are preferred. Particularly, methoxy, ethoxy, n-propoxy,isopropoxy, and n-butoxy are preferred. Examples of phenylalkyloxygroups represented by R³, which may be substituted by halogen or loweralkyl, include phenyl C1-C6 alkyloxy in which the benzene nucleus may besubstituted by a halogen atom or a C1-C6 alkyl group, with phenyl C1-C4alkyloxy in which the benzene nucleus may be substituted by a halogenatom or a C1-C4 alkyl group being more preferred. Examples ofparticularly preferred R³ groups include benzyloxy, chlorobenzyloxy,fluorobenzyloxy, bromobenzyloxy, methylbenzyloxy, ethylbenzyloxy,isopropylbenzyloxy, n-butylbenzyloxy, phenetyloxy, methylphenetyloxy,phenylpropyloxy, and phenylbutyloxy. n is an integer of from 1 to 5, andparticularly preferably from 1 to 3.

The compound (1) of the present invention forms a salt together with anacid or a base. Examples of salts formed together with acids include,but are not limited to, those formed with a variety of acids includingmineral acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, nitric acid, and phosphoric acid; organic acidssuch as formic acid, acetic acid, propionic acid, oxalic acid, malonicacid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonicacid; and acidic amino acids such as aspartic acid and glutamic acid.Examples of salts formed together with bases include, but are notlimited to, those formed with inorganic bases such as sodium, potassium,magnesium, calcium, aluminum, and zinc; those formed with basic aminoacids such as lysin and ornithine; and ammonium salts.

The present invention encompasses a variety of solvates of the compoundof formula (1), substances of formula (1) having crystallinepolymorphism, and R- and S- optical isomers, not to speak of racemiccompounds of the formula (1) compounds. Particularly when R² in formula(1) is phenyl which may have a substituent, the carbon atom to which theR² is bound becomes an asymmetric carbon atom, thereby providing opticalisomerism.

The compound (1) of the present invention may be prepared by a varietyof synthesis methods, making use of characteristics on the basis of thebackbone structure and kinds of substituents. Typical preparationmethods (methods A, B, and C) therefor will be described below. Inconnection to this, it should be noted that the compounds of the presentinvention can be prepared via any one of methods A, B, and C, or by anymethod that is accorded with these methods.

Method A

According to method A, the compound (1) of the present invention isprepared through the following steps (Step A1 to Step A6). ##STR3##(wherein each of X¹ and X² represents halogen; Y represents halogen orhydroxy; R^(3a) represents hydrogen, hydroxy, lower alkyl, lower alkoxy,or phenylalkyloxy which may be substituted by halogen or lower alkyl;and R¹, R², R³, R⁴, R⁵ and n have the same meanings as defined above).

Respective steps will next be described.

Step A1:

Compound (4) can be prepared via a Friedel-Crafts reaction of acidchloride derivative (2) and N-phenylsulfonylindole (3). Under normalcircumstances, the reaction is preferably performed in a solvent whichdoes not affect the reaction in the presence of a Lewis acid. As a Lewisacid, tin tetrahalides such as tin tetrachloride and tin tetrabromide;aluminum halides such as aluminum chloride and aluminum bromide; andboron trihalides such as boron trichloride and boron trifluoride arepreferred. Examples of solvents include alkylene halides such asmethylene chloride and ethylene chloride; and carbon disulfide. Thereaction temperature is not particularly limited, and thus the reactionmay be performed while cooling, at room temperature, or with heat.

When compound (2) is used in which R^(3a) is hydroxy, compound (4) canbe obtained by performing o-alkylation or o-phenylalkylation aftercompletion of a Friedel-Crafts reaction. This may be performed through areaction using alkyl halide or phenyl alkyl halide; a reaction using anester of alkyl sulfonic acid or alkyl sulfuric acid; or a reaction usinga diazo compound.

Step A2:

Benzoyl indole derivative (6) can be prepared by reacting compound (4)with halohydrin derivative (5). The reaction is preferably performed ina solvent which does not affect the reaction, such as acetone,N,N-dimethylformamide, or methylene chloride, in the presence of a basesuch as an alkali metal carbonate, e.g., potassium carbonate or sodiumcarbonate; trialkylamine, e.g., triethylamine or diisopropyletylamine;or a pyridine such as pyridine, lutidine, or 4-dimethylaminopyridine.The reaction is generally performed at room temperature or with heat.

Step A3:

Halide (7) can be prepared by the hydrogenation of the benzoyl indolederivative (6). The hydrogenation reaction may be performed by causing areaction with a carbon tetrahalide such as carbon tetrabromide or carbontetrachloride and triphenylphosphine in a solvent such as methylenechloride or acetonitrile. Alternatively, hydrogenation may be performedusing phosphorus tribromide, thionyl chloride, etc. The reactiontemperature is not particularly limited, and the reaction may beperformed while cooling, at room temperature, or with heat.

Step A3':

Halide (7) may also be prepared by reacting compound (4) with compound(8). When Y in compound (8) is hydroxy, the reaction may be performed ina solvent such as ether or tetrahydrofuran in the presence oftriphenylphosphine and diethylazodicarboxylate (DEAD). The reactiontemperature is not particularly limited, and thus the reaction may beperformed while cooling, at room temperature, or with heat.

When an optically active compound (8) is used in the above reaction, thereaction proceeds without causing racemation. Therefore, in the case inwhich an optically active compound among the compounds of formula (1) ofthe present invention is to be prepared, it is preferred that anoptically active compound (8) be used in this reaction.

When Y in compound (8) is a halogen atom, halide (7) can be prepared ina manner similar to that described in Step A2. Y is preferably a halogenatom that is more reactive than X².

Step A4:

Compound (10) can be prepared via condensation of halide (7) using aphenyl piperazine derivative (9). The reaction may be performed underconditions similar to those described in Step A2. When halide (7) is achloro-modification, potassium iodide is preferably added to thereaction.

Step A5:

Ester (11) can be prepared by heating compound (10) in methanol orethanol in the presence of a base such as sodium hydroxide, potassiumhydroxide, sodium carbonate, or potassium carbonate, to therebyeliminate the protective phenylsulfonyl group, and subsequently byperforming a reaction with ethyl 4-bromobutyrate. The reactionconditions are similar to those employed in Step A2.

Step A6:

The compound (1) of the present invention can be prepared throughhydrolysis of the ester (11). The reaction is usually performed inmethanol, ethanol, tetrahydrofuran, or a solvent mixture containing anyone of these organic solvents and water, in the presence of a base suchas an alkali metal hydroxide, e.g., sodium hydroxide or potassiumhydroxide; or an alkali metal carbonate, e.g., sodium carbonate orpotassium carbonate, at room temperature, while applying mild heat, orwith heat.

Method B

According to method B, the compound (1) of the present invention isprepared through the following steps (Step B1 to Step B4) using, as astarting compound, compound (12) which is described in WO93/02050.##STR4## (wherein Y represents halogen or hydroxy; and R¹, R², R³, R⁴,R⁵, X¹, X² and n have the same meanings as defined above).

Steps B1 , B2, B2', B3, and B4 are performed in manners similar to stepsA2, A3, A3', A4, and A6, respectively.

Method C

According to method C, the compound of the present invention is preparedthrough the following steps (Step C1 to Step C4). ##STR5## (wherein X²,R¹, R², R³, R^(3a), R⁴, R⁵ and n have the same meanings as definedabove).

Steps C1, C2, C3, and C4 are performed in manners similar to steps A1,A4, A5 and A6, respectively.

In any case of method A, B, or C, the last hydrolysis step is generallyperformed in the presence of a base. Therefore, the compound (1) of thepresent invention can be separated as a salt of the base that is used Toconvert this into a free carboxylic acid, neutralization using an acidis performed. Transformation into other salts is performed byconventional methods.

The thus-obtained compound (1) of the present invention exhibitsexcellent α₁ -adrenergic receptor blocking action and testosterone5α-reductase inhibitory action, and is very safe as described below.Therefore, the compound is useful as a preventive or a remedy forprostatic hypertrophy and disorders accompanying the same, such asurination disorder, male pattern alopecia, and acne.

The compound (1) of the present invention, together withpharmaceutically accepted carriers and auxiliaries, may be formulatedinto preparations for oral or parenteral administration. Whenpreparations for oral administration are formed, the present compound issuitably combined with vehicles such as lactose, mannitol, cornstarch,or crystalline cellulose; binders such as cellulose derivatives, gumarabic, and gelatin; disintegrants such as carboxymethylcellulose•Ca;and lubricants such as talc and magnesium stearate, and is formed intotablets, powders, granules, capsules, etc. These solid preparations maybe formed into enteric preparations using a coating base such ashydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, cellulose acetate phthalate, or a methacrylatecopolymer. Regarding preparations for parenteral administration, whenthe compound is combined with water, ethanol, glycerol, or customarysurfactants, there may be prepared injection liquids; or when asuppository base is combined, suppositories are prepared.

The dosage may vary depending on age, body weight, symptom of thedisease, goal of the treatment, manner of administration, period ofadministration, etc. Generally, in the case of oral administration, thecompound is administered in amounts of 1-2000 mg/day, preferably 10-300mg/day, as divided in 1 to 3 times a day.

EXAMPLES

The present invention will next be described by way of examples, whichshould not be construed as limiting the invention. MS data was obtainedby fast atom bombardment mass spectroscopy (FABMS) unless otherwisespecified.

Example 1 (Method A)

Potassium 4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl} butanoate

Step 1:

4-Hydroxy-3-methoxybenzoyl chloride, which was prepared from4-hydroxy-3-methoxybenzoic acid (1.01 g) and thionyl chloride (0.53 ml),was dissolved in dichloroethane (10 ml). The resultant solution wasadded on ice to a suspension of aluminum chloride (2.08 g) indichloroethane (20 ml). Following, 1-(phenylsulfonyl)indole (1.85 g) indichloroethane (10 ml) was added to the resultant with cooling on icebath and stirred for 1.5 hours at room temperature. The reaction mixturewas poured into 1N HCl (100 ml). The precipitate was collected byfiltration and washed with water and methanol, obtaining 1.22 g of3-(4-hydroxy-3-methoxybenzoyl)-1-(phenylsulfonyl)-indole as colorlesscrystals.

mp: 215°-217° C. (decomposed); MS(m/z):408(MH⁺); IR(KBr)cm⁻¹ :3250,1622, 1582NMR(DMSO-d₆)δ:3.87(s,3H), 6.99(d, 1H) 7.36˜7.50(m, 4H),7.58˜7. 67(m, 2H) 7.72˜7.78(m, 1H), 7.99˜8.20(m, 4H) 8.29(s, 1H),10.06(s, 1H)

Step 2:

1-(4-Methylphenyl)-1,3-propanediol (1.00 g) was dissolved in methylenechloride (30 ml), and 47% hydrobromic acid (3 ml) was added to theresultant solution. After stirring the mixture for 1 hour at roomtemperature, water was added to separate an organic layer. The organiclayer was sequentially washed with saturated sodium bicarbonate solutionand brine in this order and dried to remove the solvent. The residue wasdissolved in acetone (15 ml). To the solution were added3-(4-hydroxy-3-methoxybenzoyl)-1-(phenylsulfonyl)indole (1.08 g)obtained in Step 1 and potassium carbonate (1.65 g). The mixture wasrefluxed for 2 hours. After cooling, the reaction mixture was filtered,and then the solvent was distilled off. The residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=3:1), obtaining1.04 g of 3-{3-methoxy-4-1-(4-methylphenyl)-3-hydroxypropoxy!benzoyl)-1-(phenylsulfonyl)indole asa yellow oily substance.

MS (m/z): 556(MH⁺); IR (KBr) cm⁻¹ :3600˜3250, 1636, 1593, 1578; NMR(CDCl₃)δ:2.10˜2.40(m, 6 H) 3.80˜3.98(m, 5H), 5.40(dd, 1H) 6.74(d, 1H),7.13˜7.60(m, 11H) 7.86˜8.03(m, 4H), 8.18˜8.23(m, 1H)

Step 3:

3-{3-Methoxy-4- 1-(4-methylphenyl)-3-hydroxypropoxy!benzoyl}-1-(phenylsulfonyl)indole (0.99 g) obtained in Step 2 wasdissolved in methylene chloride (10 ml). Triphenylphosphine (0.71 g) andcarbon tetrabromide (1.01 g) were added to the resultant solution whilecooling on ice bath and stirred for 30 minutes at room temperature.Saturated sodium bicarbonate solution was added to the reaction mixtureto separate an organic layer. The organic layer was washed with brineand then dried. The solvent was distilled off. The residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=9:1),obtaining 0.65 g of 3{(3-methoxy-4-3-bromo-1-(4-methylphenyl)propoxy!benzoyl}-1-(phenylsulfonyl )indole asa light brown oily substance.

MS (m/z) : 618 (MH⁺); IR (KBr) cm⁻¹ :1636, 1593, 1578; NMR(CDCl₃)δ:2.27˜2.76 (m, 5H) 3.47˜3.79(m, 2H), 3.96 (s, 3H) 5.46 (dd, 1H),6.83 (d, 1H) 7.16˜7.61(m, 11H), 7.87˜7.93(m, 2H) 7.96˜8.02 (m, 2 H),8.18˜8.23 (m,1H)

Step 4:

3-{3-Methoxy-4- 3-bromo-1-(4-methylphenyl)propoxybenzoyl}-1-(phenylsulfonyl)indole (0.59 g) obtained in Step 3 wasdissolved in N,N-dimethylformamide (6 ml). 1-(2-Methoxyphenyl)piperazine(0.22 g) and potassium carbonate (0.20 g) were added to the resultantsolution and stirred for 3 hours at 60° C. After cooling, water wasadded to the reaction mixture, followed by extraction with ethylacetate. The extract was washed with brine and then dried. The solventwas distilled off. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1), obtaining 0.56 g of3{-methoxy -4-(1-(4-methylphenyl) -3- 4- (2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}-1-(phenylsulfonyl)indole as a lightyellow oily substance.

MS (m/z):730(MH⁺); IR (KBr) cm⁻¹ :1636, 1593, 1578; NMR(CDCl₃)δ:2.04˜2.47(m, 5H) 2.61(t, 2H), 2.63˜2.73(br, 4H) 3.07˜3.16(br,4H), 3.36(s, 3H) 3.96(s, 3H), 5.39(dd, 1H) 6.84˜7.03(m, 5H),7.14˜7.59(m, 11H) 7.85˜7.92(m, 2H), 7.96˜8.01(m, 2H) 8.18˜8.2 2(m, 1H)

Step 5:

3-{3-Methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}-1-(phenylsulfonyl)indole(0.49 g) obtained in Step 4 was dissolved in methanol (10 ml). Potassiumhydroxide (0.60 g) was added to the resultant solution and refluxed for1 hour. After cooling, the solvent was distilled off. Water was added tothe residue, followed by extraction with methylene chloride. The extractwas washed with brine and then dried. The solvent was distilled off,obtaining 0.37 g of 3-{3-methoxy-4-{l-(4-methylphenyl)-3-4-(2-methoxyphenyl) piperazin-1-yl!propoxy}benzoyl}indole as a lightyellow oily substance.

MS (m/z): 590 (MH⁺); IR (KBr) cm⁻ :1595, 1576; NMR (CDCl₃)δ:2.00˜2.45(m,5H) 2.50˜2.72(m, 6H) 3.04-3.1 6(br, 4H) 3.84(s, 3H)3.88(s, 3 H), 5.32(t,1H) 6.73˜7.03(m, 5H)7.10˜7.44(m, 9H) 7.57(s, 1H),8.30˜3.38(m, 1H)

Thus-obtained 3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indole (0.36 g) wasdissolved in N,N-dimethylformamide (5 ml). 4-Bromo ethyl butylate (0.12g) and potassium carbonate (0.13 g) were added to the resultant solutionand stirred overnight at room temperature. Water was added to thereaction mixture, followed by extraction with ethyl acetate. The extractwas washed with brine and then dried. The solvent was distilled off. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:1), obtaining 0.28 g of ethyl4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)-piperazin-1-yl!propoxy}benzoyl}indol -1-yl}butanoateas a light yellow oily substance.

MS (m/z): 704 (MH⁺); IR (KBr) cm⁻¹ :1730, 1624, 1595; NMR(CDCl₃)δ:1.19(t, 3H), 2.05˜2.46(m, 9H), 2.56˜2.73(m, 6H), 3.06˜3.15(br,4H), 3.86(m, 3H), 3.95(s, 3H), 4.08(q, 2H), 4.23(t, 2H), 5.35(dd, 1H),6.77˜7.03(m, 5H), 7.13˜7.46(m, 9H), 7.55(s 1H), 8.33˜8.39(m, 1H)

Step 6:

Ethyl 4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl} indol-1-yl}butanoate(2.00 g) was dissolved in ethanol (20 ml). Potassium hydroxide (0.64 g)was added to the resultant solution and stirred overnight at roomtemperature. After removing the solvent, the residue was purified usingan HP-20 column, obtaining 1.34 g of potassium4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoateas amorphous powder.

MS (m/z):714(MH⁺); IR (KBr) cm⁻¹ :1595, 1573; NMR(DMSO-d₆)δ:1.84˜2.04(m, 5H), 2.10˜2.31(m, 4H), 2.44(t, 2H),2.45˜2.55(br, 4H), 2.92˜3.01(br, 4H), 3.76(s, 3H), 3.89(s, 3H), 4.24(t,2H), 5.46(t, 1H), 6.82˜6.96(m, 5H), 7.14˜7.38(m, 8H), 7.66(d, 1H),8.00(s, 1H), 8.19˜8.24(m, 1H),

Example 2 (Method B)

4-{3-{4-{1-Phenyl-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-yl}butanoic acid

Step 1:

1-Phenyl-1,3-propanediol (6.17 g) was dissolved in toluene (200 ml) and47% hydrobromic acid (20 ml) was added to the resultant solution. Themixture was stirred for 1.5 hours at room temperature. Water was addedto the reaction mixture to separate an organic layer. The organic layerwas sequentially washed with saturated sodium bicarbonate solution andbrine in this order and then dried. The solvent was distilled off. Theresidue was dissolved in acetone (150 ml). Ethyl4-{3-(4-Hydroxybenzoyl)indol-1-yl}butanoate (6.33 g) and potassiumcarbonate (9.95 g) were added to the resultant solution and refluxed for20 hours.

After cooling, the reaction mixture was filtered, and then the solventwas distilled off. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), obtaining 7.38 g of ethyl4-{(3- 4-(1-phenyl-3-hydroxypropoxy)benzoyl!indol-yl}butanoate ascolorless crystals.

mp:114°-1150° C. MS (EI, m/z):485(M⁺); IR (KBr) cm⁻¹ :3600˜3300, 1728,1600NMR (CDCl₃)δ:1.20(t, 3 H), 1.79(t 1H), 2.0 6˜2.36(m 6H),3.75˜3.98(m, 2H), 4.09(q, 2H), 4.23(t, 2H), 5.48(dd, 1H), 6.94(d, 2H),7.25˜7.43(m, 8H), 7.51(s, 1H), 7.72(d, 2H), 8.33˜8.38(m, 1H)

Step 2:

Ethyl 4-{3- 4-(1-phenyl-3-hydroxypropoxy) benzoyl!indol-1-yl}butanoate(4.00 g) obtained in Step 1 was dissolved in methylene chloride (40 ml).Triphenylphosphine (3.24 g) and carbon tetrabromide (3.24 g) were addedto the resultant solution while cooling on ice bath and stirred for 30minutes at room temperature. Saturated sodium bicarbonate solution wasadded to the reaction mixture to separate an organic layer. The organiclayer was washed with brine and then dried. The solvent was distilledoff. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=5:1), obtaining 3.97 g of ethyl 4-{3-4-(3-bromo-1-phenylpropoxy)benzoyl!indol-1-yl}butanoate as colorlessoily substance.

MS (m/z)548(MH⁺); IR (neat) cm⁻¹ :1728, 1601NMR (CDCl₃)δ:1.20(t, 3H),2.1(quint, 2H), 2.25˜2.67(m, 4H), 3.45˜3.73(m, 2H), 4.09(q, 2H), 4.24(t,2H), 5.47(dd, 1H), 6.95(d, 2H), 7.26˜7.43(m, 3H), 7.52(s, 1H), 7.74(d,2H), 8.33˜8.39(m, 1H)

Step 3:

Ethyl 4-{3- 4-(3-bromo-1-phenylpropoxy)benzoyl!indol-1-yl}butanoate(1.97 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (20ml). 1-(2-Methoxyphenyl) piperazine (0.83 g) and potassium carbonate(0.75 g) were added to the resultant solution and stirred overnight at60° C. After cooling, water was added to the reaction mixture, followedby extraction with ethyl acetate. The resultant extract was washed withbrine and then dried. The solvent was distilled off. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1), obtaining 1.95 g of ethyl 4-{3-{4-{1-phenyl-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoateas a colorless oily substance.

MS (m/z) 660(MH⁺); IR (KBr) cm⁻¹ :1730, 1599; NMR (CDCl₃)δ: 1.20(t, 3H),2.01˜2.37(m, 6H), 2.52˜2.72(m, 6H), 3.06˜3.17(br, 4H), 3.86(s, 3H),4.09(q, 2H), 4.23(t, 2H), 5.37(dd, 1H), 6.84˜7.04(m, 6H), 7.25˜7.43(m,8H), 7.52(s, 1H), 7.74(d, 2H), 8.33˜8.39(m, 1H),

Step 4:

Ethyl 4-{3-{4-{1-phenyl-3- 4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate (1.89 g) obtained inStep 3 was dissolved in ethanol (20 ml). Potassium hydroxide (0.80 g)was added to the resultant solution and stirred for 3 hours at roomtemperature. After adding acetic acid (2 ml) to the reaction mixture,the solvent was distilled off. Water was added thereto, followed byextraction with ethyl acetate. The resultant extract was washed withbrine and dried. The solvent was distilled off. The residue was purifiedby silica gel column chromatography (methylene chloride: methanol=40:1),obtaining 1.68 g of 4-{3-{4-{1-phenyl-3-4-(2-methoxyphenyl)piperazin-1-yl! propoxy}benzoyl}indol-1-yl}butanoicacid as amorphous powder.

MS (m/z):632(MH⁺); IR (KBr) cm⁻¹ :3500˜3250, 1721, 1597; NMR(CDCl₃)δ:2.0 8-2.3 2(m, 4H), 2.50˜2.61(m, 2H), 3.00˜3.55(m, 10H),3.84(s, 3H), 4.23(t, 2H), 5.56(t, 1H), 6.85˜7.10(m, 6H), 7.22˜7.43(m,8H), 7.52(s 1H), 7.72(d, 2H), 8.34˜8.42(m, 1H)

Examples 3 to 27

Compounds of the following Examples 3 to 27 were synthesized fromadequate material compounds in accordance with the method of Example 1or 2.

Example 3

Potassium 4-{3-{4-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS (m/z):594(MH⁺); IR (KBr) cm⁻ :1731, 1599; NMR (DMSO-d₆)δ:1.90˜2.10(m,4H), 2.24(t 2H), 2.40-2.70(br, 6H), 2.93˜3.06(br, 4H), 3.78(s, 3H),4.15(t, 2H), 4.31(t, 2H), 8.85˜6.98(m, 4H), 7.08(d, 2H), 7.22˜7.35(m,2H), 7.63(d, 1H), 7.81(d, 2H), 8.01(s, 1H), 8.22˜8.27(m, 1H)

Example 4

Potassium 4-{3-{4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS (m/z):684(MH⁺); IR (KBr) cm⁻¹ :1597; NMR (DMSO-d ₆)δ:1.84˜2.22(m,6H), 2.27(s, 3H), 2.44(t, 2H), 2.45˜2.55(br, 4H), 2.90˜3.00(br, 4H),3.76(s, 3H), 4.24(t, 2H), 5.47(t, 1H), 6.82˜6.95(m, 4H), 7.02(d, 2H),7.16˜7.36(m, 6H), 7.65(d, 1H), 7.71(d, 2H), 7.95(s, 1H), 8.18˜8.23(m,1H),

Example 5

4-{3-{4-{1-Phenyl-3-4-(2-isopropoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoicacid

MS (m/z):660(MH⁺); IR (KBr) cm⁻¹ :3650˜3300, 1720, 1599; NMR(CDCl₃)δ:1.32(s, 3H), 1.34(s, 3H), 2.05˜2.42(m, 6H), 2.80˜3.02(m, 6H),3.10˜3.28(br, 4H), 4.19(t, 2H), 4.57(sept, 1H), 5.33(dd, 1H),6.80˜7.00(m, 6H), 7.20˜7.42(m, 8H), 7.53(s, 1H), 7.71(d, 2H),8.33˜8.39(m, 1H)

Example 6

4-{3-{4-{1-Phenyl-4-4-(2-methoxyphenyl)piperazin-1-yl!butoxy}benzoyl}indol-1-yl}butanoicacid

MS (m/z):646(MH⁺); IR (KBr) cm⁻¹ :3500˜3300, 1725, 1597; NMR(CDCl₃)δ:1.90˜2.32(m, 8H), 2.95˜3.65(m, 10H), 3.84(s, 3H), 4.23(t, 2H),5.26(t, 1H), 6.84˜7.10(m, 6H), 7.23˜7.42(m, 8H), 7.52(s, 1H), 7.72(d,2H), 8.35˜8.41(m, 1H),

Example 7

4-{3-{4-{1-Phenyl-4-4-(2-isopropoxyphenyl)piperazin-1-yl!butoxy}benzoyl}indol-1-yl}butanoicacid

MS (m/z):674(MH⁺); IR (KBr) cm⁻¹ :3300, 1722, 1599; NMR (CDCl₃)δ:1.34(d,6H), 1.85˜2.30(m, 8H), 2.87˜3.03(m, 2H), 3.06˜3.25(br, 4H),3.30˜3.44(br, 4H), 4.22(t, 2H), 4.57(sept, 1H), 5.25(t, 1H),6.82˜7.03(m, 6H), 7.22˜7.42(m, 8H), 7.53(s, 1H), 7.72(d, 2H),8.36˜8.41(m, 1H)

Example 8

Potassium 4-{3-{4-{1-(4-methylphenyl)-3-4-(2-isopropoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS (m/z):712 (MH⁺); IR (KBr) cm⁻¹ :1597; NMR (DMSO-d₆)δ:1.24(d, 6H),1.86˜2.24(m, 6H), 2.27(s, 3H), 2.44(t, 2H) 2.45˜2.55(br, 4H),2.91˜3.01(br, 4H), 4.25(t, 2H), 4.57(sept, 1H), 5.48(t, 1H),6.84˜6.90(m, 4H), 7.01(d, 2H), 7.13˜7.37(m, 6H), 7.63(d, 1H), 7.71(d,2H), 7.96(s, 1H), 8.19˜8.24(m 1H),

Example 9

Potassium 4-{3-{4-{1-(4-ethylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS (m/z):698(MH⁺); IR (KBr) cm⁻¹ :1597; NMR (DMSO-d₆)δ:1.16(3H),1.85˜2.25(m, 6H), 2.45(t, 2H), 2.46˜2.54(br, 4H), 2.58(q, 2H),2.90˜3.00(br, 4H), 4.24(t, 2H), 5.48(t, 1H), 6.83˜6.90(m, 4H), 7.02(d,2H), 7.16˜7.40(m, 6H), 7.64(d, 1H), 7.71(d, 2H), 7.95(s, 1H),8.18˜8.23(m, 1H)

Example 10

Potassium 4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-ethoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS (m/z):728(MH⁺); IR (KBr) cm⁻¹ :1598; NMR (DMSO-d₆)δ:1.33(t, 3H),1.84˜2.25(m, 6H), 2.27(s, 3H), 2.44(t, 2H), 2.45˜2.55(br, 4H),2.95˜3.05(br, 4H), 3.89(s, 3H), 3.99(q, 2H), 4.24(t, 2H), 5.45(t 1H),6.82˜6.95(m, 5H), 7.13˜7.37(m, 8H), 7.64(d, 1H), 7.99(s, 1H),8.19˜8.24(m, 1H),

Example 11

Potassium 4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-isopropoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS (m /z):742(MH⁺); IR(KBr)cm⁻¹ :1593, 1578; NMR (DMSO-d₆)δ:1.22(s, 3H),1.25(s, 3H), 1.84˜2.03(m, 5H), 2.10˜2.30(m, 4H), 2.44(t, 2H),2.45˜2.55(br, 4H), 2.92˜3.04(br, 4H), 3.89(s, 3H), 4.24(t, 2H),4.57(sept, 1H), 5.46(t, 1H), 6.83˜6.95(m, 5H), 7.13˜7.38(m, 3H), 7.64(d,1H), 8.00(s, 1H), 8.20˜8.24(m 1H),

Example 12

4-{3-{3-methoxy-4-{1-(4-ethylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoicacid

MS (m /z):690(MH⁺); IR(KBr)cm⁻¹ :1718, 1595; NMR(CDCl₃)δ:1.18(t, 3H),2.05˜2.50(m, 6H), 2.59(q, 2H), 2.94(t, 2 H), 2.95˜3.06(b, 4H),3.17˜3.27(br, 4H), 3.34(s, 3H), 3.91(s, 3H), 4.20(t 2H), 5.33(t, 1H),6.78˜6.91(m, 12H), 6.98˜7.05(m, 1H), 7.12(d, 2H), 7.24˜7.31(m, 5H),7.36˜7.42(m, 2H), 7.56(s, 1H), 8.35˜3.40(m, 1H)

Example 13

Potassium 4-{3-{3-methoxy-4-{1-(4-isobutylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):756(MH⁺); IR(KBr)cm⁻¹ :1598; NMR(DMSO-d₆)δ:0.84(d, 6H),1.72˜2.28(m, 7H), 2.35˜2.50(m, 2H), 2.42(t, 2H), 2.46˜2.56(br, 4H),2.88˜3.00(br, 4H), 3.76(s, 3H), 3.89(s, 3H), 4.25(t, 2H), 5.46(t, 1H),6.84˜6.97(m, 5H), 7.10˜7.39(m, 3H), 7.62(d, 1H), 8.00(s, 1H),8.19˜8.25(m, 1H)

Example 14

Potassium 4-{3-{3-methoxy-4-{1-phenyl-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):700(MH⁺); IR(KBr)cm⁻¹ :1593, 1572; NMR(DMSO-d₆)δ:1.87˜2.27(m,6H), 2.46(t, 2H), 2.45˜2.55(br, 4H), 2.90˜3.02(br, 4H), 3.76(s 3H),3.90(s, 3H), 4.25(t, 2H), 5.51(t, 1H), 6.82˜7.00(m, 5H), 7.18˜7.50(m,8H), 7.64(d, 1H), 8.00(s, 1H), 8.20˜8.25(m, 1H)

Example 15

Potassium 4-{3-{3-methoxy-4-{1-phenyl-3-4-(2-ethoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):714(MH⁺); IR(KBr)cm⁻¹ :1593, 1572; NMR(DMSO-d₆)δ1.32(t, 3H),1.82˜2.27(m, 6H), 2.46(t, 2H), 2.45˜2.55(br, 4H), 2.93˜3.04(br, 4H),3.90(s, 3H), 3.99(q, 2H), 4.25(t 2H), 5.51(t, 1H), 6.80˜6.92(m, 4H),6.95(d, 1H), 7.18˜7.49(m, 9H), 7.66(d, 1H), 8.01(s, 1H), 8.20˜8.26(m,1H)

Example 16

Potassium 4-{3-{3-methoxy-4-{1-phenyl-3-4-(2-isopropoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):728(MH⁺); IR(KBr)cm⁻¹ :1728, 1595, 1578; NMR(DMSO-d₆)δ:1.22(s,3H), 1.25(s, 3H), 1.82˜2.26(m, 6H), 2.46(t, 2H), 2.45˜2.55(br, 4H),2.93˜3.03(br, 4H), 3.90(s, 3H), 4.24(t, 2H), 5.51(t, 1H), 6.87(s, 4H),6.94(d, 1H), 7.18˜7.47(m, 9H), 7.65(d, 1H), 8.01(s, 1H), 8.20˜8.26(m,1H)

Example 17

4-{3-{3-Methoxy-4-{1-phenyl-4-4-(2-methoxyphenyl)-piperazin-1-yl!butoxy}benzoyl}indol-1-yl}butanoicacid

MS(m/z):676(MH⁺) IR(KBr)cm⁻¹ :3431, 1718, 1595; NMR(CDCl₃)δ:1.91˜2.28(m,8H), 2.94˜3.06(br, 2H), 3.10˜3.22(br, 4H), 3.30˜3.40(br 4H), 3.84(s,3H), 3.91(s, 3H), 4.21 (t, 2H), 5.27(t, 1H), 6.78(d, 1H), 6.83˜6.94(m,3H), 6.98˜7.07(m, 1H), 7.20˜7.43(m, 10H), 7.56(s, 1H), 8.35˜8.40(m, 1H)

Example 18

Potassium 4-{3-{3-methoxy-4-{1-phenyl-5-4-(2-methoxyphenyl)piperazin-1-yl!pentyloxy}benzoyl}indol-1-yl}butanoate

MS(m/z):728(MH⁺); IR(KBr)cm⁻¹ :1593; NMR(DMSO-d₆)δ:1.30˜1.58(m, 4H),1.75˜2.10(m, 6H), 2.29(t, 2H), 2.40˜2.50(br, 4H), 2.87˜2.97(br, 4H),3.75(s, 3H), 3.89(s, 3H), 4.24(t, 2H), 5.42(t, 1H), 6.83˜6.97(m, 5H),7.17˜7.45(m, 9H), 7.65(d, 1H), 7.99(s, 1H), 8.19˜8.24(m, 1H)

Example 19

Potassium 4-{3-{3-methoxy-4-{1-(4-bromophenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):778(MH⁺); IR(KBr)cm⁻¹ :1595, 1572; NMR(DMSO-d₆)δ:1.83˜2.25(m,6H), 2.45(t, 2H), 2.45˜2.55(br, 4H), 2.92˜3.00(br, 4H), 3.76(s, 3H),3.90(s, 3H), 4.25(t, 2H), 5.52(t, 1H), 6.82˜6.97(m, 5H), 7.18˜7.45(m,6H), 7.57(d, 2H), 7.67(d, 1H), 8.01(s, 1H), 8.20˜8.24(m, 1H)

Example 20

Potassium 4-{3-{4-{1-(4-methoxyphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):700(MH⁺); IR(KBr)cm⁻¹ :1597, 1570; NMR(DMSO-d₆)δ:1.85˜2.21(m,6H), 2.42(t, 2H), 2.44˜2.54(br, 4H), 2.90˜3.01(br, 4H), 3.73(s, 3H),3.76(s, 3H), 4.24(t, 2H), 5.47(t, 1H), 6.83˜6.97(m, 5H), 7.03(d, 2H),7.18˜7.30(m, 2H), 7.38(d, 2H), 7.66(d, 1H), 7.72(d, 2H), 7.95(s, 1H),8.19˜8.24(m, 1H)

Example 21

4-{3-{3,5-Dimethoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoicacid

MS(m/z):706(MH⁺) IR(KBr)cm⁻¹ :3600˜3200, 1719, 1624, 1578;NMR(DMSO-d6)δ:1.95˜2.55(m, 8H), 2.90˜3.50(br, 8H), 3.77(s, 3H), 3.80(s,6H), 4.31(t, 2H), 5.44(t, 1H), 6.83˜6.98(m, 4H), 7.02(s, 2H),7.10˜7.35(m, 6H), 7.63(d, 1H), 8.09(s, 1H), 8.18˜8.23(m, 1H)

Example 22

4-{3-{2,3-Dimethyl-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoicacid

MS(m/z):674(MH⁺); IR(KBr)cm⁻¹ :1628, 1590; NMR(CDCl₃)δ:1.38˜2.82(m,15H), 2.45˜2.65(br, 6H), 2.93˜3.03(br, 4H), 3.76(s, 3H), 4.21(t, 2H),5.42(t, 1H), 6.82˜6.97(m, 4H), 7.06(d, 1H), 7.14˜7.35(m, 7H),7.57˜7.65(m, 2H), 8.19(d, 1H)

Example 23

Potassium 4-{3-{4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}-2-methylindol-1-yl}butanoate

MS(m/z):698(MH⁺) IR(KBr)cm⁻¹ :1732, 1597; NMR(CDCl₃)δ:1.60˜1.80(m, 4H),1.95˜2.05(m, 2H), 2.22(s, 3H), 2.28(s, 3H), 2.51(t, 2H), 2.54˜2.64(br,4H), 3.00˜3.10(br, 4H), 3.65˜3.75(br, 2H), 3.82(s, 3H), 5.26(t, 1H),6.70˜7.14(m, 2H), 7.19(d, 1H), 7.55(d, 2H),

Example 24

4-{3-{3-Benzyloxy-4-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoicacid

MS(m/z):662(MH⁺); IR(KBr)cm⁻¹ :1595, 1561; NMR(DMSO-d₆)δ:1.90˜2.15(m,6H), 2.40˜2.60(m, 6H), 2.90˜3.00(br, 4H), 3.77(s, 3H), 4.10˜4.30(m, 4H),5.22(s, 2H), 6.85˜6.95(m, 4H), 7.14(d, 1H), 7.22˜7.51(m, 9H),7.63˜7.66(m, 1H), 7.95(s, 1H), 8.22˜8.25(m, 1H), 13.00(br, 1H),

Example 25

Sodium 4-{3-{4-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}-3-(4-methylphenylmethoxy)benzoyl}indol-1-yl}butanoate

MS(m/z):698(MH⁺); IR(KBr)cm⁻¹ :1595, 1500; NMR(DMSO-d₆)δ:190˜2.18(m,6H), 2.30(s, 3H), 2.44˜2.59(m, 6H), 2.90˜3.00(br, 4H), 3.77(s, 3H),4.10˜4.20(m, 2H), 4.23˜4.30(m, 2H), 5.16(s, 2H), 6.85˜6.95(m, 4H),7.10˜7.45(m, 9H), 7.60˜7.66(m, 1H), 7.96(s, 1H), 820˜8.25(m, 1H),

Example 26

4-{3-{3-Benzyloxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoicacid

MS(m/z):752(MH⁺); IR(KBr)cm⁻¹ :1595, 1572; NMR(CDCl₃)δ:2.02˜2.41(m, 9H),2.75˜2.90(m, 6H), 3.06˜3.18(br, 4H), 3.83(s, 3H), 4.16(t, 2H), 5.17(s,2H), 5.24˜5.32(m, 2H), 6.80˜7.11(m, 7H), 7.20˜7.50(m, 13H), 8.36˜8.39(m,1H)

Example 27

4-{3-{3-Methoxy-4-{1-(4-fluorophenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoicacid

MS(m/z):680(MH⁺); IR(KBr)cm⁻¹ :1595, 1578; NMR(CDCl₃)δ:2.10˜2.43(m, 6H),2.78˜2.87(m, 2H), 2.90˜3.00(br, 4H), 3.12˜3.21(br, 4H), 3.84(s, 3H),3.91(s, 3H), 4.24(m, 3H), 5.32˜5.39(m 1H), 6.80˜6.91(m, 4H),6.96˜7.05(m, 3H), 7.25˜7.43(m, 7H), 7.54(s, 1H), 8.35˜8.41(m, 1H)

The structures of the compounds obtained in Examples 1 through 27 areshown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________     ##STR6##                                                                     Example No.                                                                          R1  n   R2    R3       R4  R5  M                                       __________________________________________________________________________    1      Me  2   4-MePh                                                                              3-MeO    H   H   K                                       2      Me  2   Ph    H        H   H   H                                       3      Me  2   H     H        H   H   K                                       4      Me  2   4-MePh                                                                              H        H   H   K                                       5      i-Pr                                                                              2   Ph    H        H   H   H                                       6      Me  3   Ph    H        H   H   H                                       7      i-Pr                                                                              3   Ph    H        H   H   H                                       8      i-Pr                                                                              2   4-MePh                                                                              H        H   H   K                                       9      Me  2   4-EtPh                                                                              H        H   H   K                                       10     Et  2   4-MePh                                                                              3-MeO    H   H   K                                       11     i-Pr                                                                              2   4-MePh                                                                              3-MeO    H   H   K                                       12     Me  2   4-EtPh                                                                              3-MeO    H   H   H                                       13     Me  2   4-i-BuPh                                                                            3-MeO    H   H   K                                       14     Me  2   Ph    3-Meo    H   H   K                                       15     Et  2   Ph    3-MeO    H   H   K                                       16     i-Pr                                                                              2   Ph    3-Meo    H   H   K                                       17     Me  3   Ph    3-MeO    H   H   H                                       18     Me  4   Ph    3-MeO    H   H   K                                       19     Me  2   4-BrPh                                                                              3-MeO    H   H   K                                       20     Me  2   4-MeOPh                                                                             H        H   H   K                                       21     Me  2   4-MePh                                                                              3-MeO    5-MeO                                                                             H   H                                       22     Me  2   4-MePh                                                                              2-Me     3-Me                                                                              H   H                                       23     Me  2   4-MePh                                                                              H        H   Me  K                                       24     Me  2   H     3-PhCH.sub.2 O                                                                         H   H   H                                       25     Me  2   H     3-(4-Me-PhCH.sub.2 O)                                                                  H   H   Na                                      26     Me  2   4-MePh                                                                              3-PhCH.sub.2 O                                                                         H   H   H                                       27     Me  2   4-FPh 3-MeO    H   H   H                                       __________________________________________________________________________     In the Table, Me stands for methyl, Et stands for ethyl, iPr stands for       isopropyl, iBu stands for isobutyl, Meo stands for methoxy, and Ph stands     for phenyl.                                                              

Example 28

Similar to the method of Example 2, the following pound was synthesized.

Potassium 4-{3-{3-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate##STR7##

MS(m/z):684(MH⁺); IR(KBr)cm⁻¹ :1574; NMR(DMSO-d₆)δ:1.86˜2.20(m, 6H),2.27(s, 3H), 2.44(t, 2H), 2.46˜2.56(br, 4H), 2.85˜2.95(br, 4H), 3.74(s,3H), 4.15˜4.30(m, 2H), 5.44(t, 1H), 6.75˜6.96(m, 4H), 7.10˜7.40(m, 10H),7.62˜7.68(m, 1H), 7.79˜7.82(m, 1H), 8.20˜8.26(m, 1H)

Example 29

Potassium S-4-{3-{4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propyloxy}benzoyl}indol-1-yl}butanoate

Step 1:

S-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazabololidine (5.54 g) wasdissolved in 1.0 M borane-tetrahydrofuran (120 ml) under argon whilecooling on ice bath. Subsequently, 4'-methyl-3-chloropropicophenone(36.5 g) in tetrahydrofuran (200 ml) was added dropwise over 1 hour andstirred for 30 minutes. 1N HCl (40 ml) was added to the reaction mixtureand stirred for a while. Then, the solvent was distilled off. 1N HCl wasadded to the residue, followed by extraction with ethyl acetate. Theextract was sequentially washed with saturated sodium bicarbonatesolution and brine in this order and then dried. The solvent wasdistilled off. The residue was recrystallized with n-hexane (200 ml),obtaining 17.3 g of R-(+)-3-chloro-1-(4-methylphenyl)-1-propanol ascolorless crystals.

mp: 48°-50° C.; MS(EI, m/z):184, 186(M⁺); IR(KBr)cm⁻¹ :3300;NMR(CDCl₃)δ:2.00˜2.30(m, 2H), 3.50˜3.60(m, 1H), 3.67˜3.78(m, 1H),4.90(quint., 1H), 7.15˜7.30(m, 4 H) α!_(D) +22.0°(c=1, CHCl₃)

Step 2:

R-(+)-3-chloro-1-(4-methylphenyl)-1-propanol (16.6 g) obtained in Step 1and ethyl 4- 3-(4-hydroxybenzoyl)indol-1-yl!butanoate (31.7 g) weredissolved in tetrahydrofuran (350 ml). Triphenylphosphine (28.3 g) anddiethylazodicarboxylate (20 ml) were added to the resultant solutionwhile cooling on ice bath and stirred for 3 hours at room temperature.After removing the solvent, the residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=4:1), obtaining 29.0 g ofethyl S-4-{3-{4-3-chloro-1-(4-methylphenyl)propoxy!benzoyl}indol-1-yl}butanoate as ayellow oily substance.

MS(m/z):518, 520(MH⁺); IR(neat) cm⁻¹ :1732, 1601, 1572;NMR(CDCl₃)δ:1.19(t, 3H), 2.10˜2.35(m, 8H), 2.42˜2.56(m, 1H),3.55˜3.65(m, 1H), 3.74˜3.35(m, 1H), 4.09(q, 2H), 4.21(t, 2H), 5.45(dd,1H), 6.94(d, 2H), 7.16(d, 2H), 7.25˜7.41(m, 5H), 7.51(s, 1H), 7.72(d,2H), 8.33˜3.39(m, 1H)

Step 3:

Ethyl S-4-{3-{4-3-chloro-1-(4-methylphenyl)propoxy!benzoyl}indol-1-yl}butanoate (29.0 g)obtained in Step 2 was dissolved in N,N-dimethylformamide (300 ml).1-(2-Methoxyphenyl)piperazine (12.9 g), potassium carbonate (15.5 g),and potassium iodide (37.2 g) were added to the resultant solution andstirred overnight at 60° C. After cooling, water was added to thereaction mixture, followed by extraction with ethyl acetate. Theresultant extract was washed with brine and then dried. The solvent wasdistilled off. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=2:1), obtaining 24.9 g of ethylS-4-{3-{4-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoateas a light yellow oily substance.

MS(m/z):674(MH⁺) IR(KBr)cm⁻ :1732, 1599, 1570; NMR(CDCl₃)δ:1.20(t, 3H),1.98˜2.36(m, 9H), 2.50˜2.72(m, 6H), 3.05˜3.16(br, 4H), 3.86(s, 3H),4.09(q, 2H), 4.23(t, 2H), 5.33(dd, 1H), 6.84˜7.06(m, 6H), 7.25˜7.44(m,4H), 7.52(s, 1H), 7.73(d, 2H), 8.33˜8.38(m, 1H), α!_(D) 20.1° (c=1,CHCl₃)

Step 4:

Ethyl S-4-{3-{4-{1-(4-Methylphenyl)-3-4-(2-methoxyphenyl)-piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate(11.0 g) obtained in Step 3 was dissolved in tetrahydrofuran (50 ml).Ethanol (60 ml) and potassium hydroxide (2.75 g) were added to theresultant solution and stirred overnight at room temperature. Afterremoving the solvent, the residue was purified using an HP-20 column,obtaining 9.58 g of potassium S-4-{3-{4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoateas amorphous powder.

MS(m/z):684(MH⁺); IR(KBr)cm⁻¹ :1597; NMR(DMSO-d₆)δ:1.84˜2.22(m, 6H),2.27(s, 3H), 2.44(t, 2H), 2.45˜2.55(br, 4H), 2.90˜3.00(br 4H), 3.76(s,3H), 4.24(t, 2H), 5.47(t, 1H), 6.82˜6.95(m, 4H), 7.02(d, 2H),7.16˜7.36(m, 6H), 7.65(d, 1H), 7.71(d, 2H), 7.95(s, 1H), 8.18˜8.23(m,1H)

Example 30

Potassium R-4-{3-{4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propyloxy}benzoyl}indol-1-yl}butanoate

Step 1:

R-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (885 mg) wasdissolved in 1.0M borane-tetrahydrofuran (18 ml) under argon whilecooling on ice bath. Subsequently, 4'-methyl-3-chloropropiophenone (5.48g) in tetrahydrofuran (60 ml) was added dropwise over 30 minutes andstirred for 30 minutes. 1N HCl (10 ml) was added to the reaction mixtureand stirred for a while. Then, the solvent was distilled off. 1N HCl wasadded to the residue, followed by extraction with ethyl acetate. Theextract was sequentially washed with saturated sodium bicarbonatesolution and brine in this order and then dried. The solvent wasdistilled off. The residue was recrystallized with n-hexane (30 ml),obtaining 2.76 g of S-(-)-3-chloro-1-(4-methylphenyl)-1-propanol ascolorless crystals.

Step 2:

S-(-)-3-chloro-1-(4-methylphenyl)-1-propanol (1.44 g) and ethyl 4-3-(4-hydroxybenzoyl)indol-1-yl!butanoate (2.74 g) were dissolved intetrahydrofuran (30 ml). Triphenylphosphine (2.46 g) anddiethylazodicarboxylate (1.72 ml) were added to the resultant solutionwhile cooling on ice and stirred for 3 hours at room temperature. Afterremoving the solvent, the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=4:1), obtaining 2.53 g of ethylR-4-{3-{4-3-chloro-1-(4-methylphenyl)propoxy!benzoyl}indol-1-yl}butanoate as ayellow oily substance.

Subsequently, potassium R-4-{3-{4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoatewas obtained in a manner similar to that described in Steps 3 and 4 ofExample 29.

MS(m/z):684(MH⁺); IR(KBr)cm⁻¹ :1597; NMR(DMSO₆)δ:1.84˜2.22(m, 6H),2.27(s, 3H), 2.44(t, 2H), 2.45˜2.55(br, 4H), 2.90˜3.00(br 4H), 3.76(s,3H), 4.24(t, 2H), 5.47(t, 1H), 6.82˜6.95(m, 4H), 7.02(d, 2H),7.16˜7.36(m, 6H), 7.65(d, 1H), 7.71(d, 2H), 7.95(s, 1H), 8.18˜8.23(m,1H)

Example 31

Potassium S-4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

R-(+)-3-chloro-1-(4-methylphenyl)-1-propanol (430 mg) obtained in Step 1of Example 29 and 1-phenylsulfonyl-3-(3-methoxy-4-hydroxybenzoyl)indole(950 mg) were dissolved in tetrahydrofuran (10 ml). Triphenylphosphine(733 mg) and diethylazodicarboxylate (0.5 ml) were added to theresultant solution and stirred for 1 hour at room temperature. Afterremoving the solvent, the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=6:1), obtaining 880 mg ofS-1-phenylsulfonyl-3-{3-methoxy-4-3-chloro-1-(4-methylphenyl)propoxy!benzoyl}indole as a yellow oilysubstance.

MS(m/z):574, 576(MH⁺); IR(KBr)cm⁻¹ :1638, 1595, 1580;NMR(CDCl₃)δ:2.20˜2.37(m, 4H), 2.53˜2.67(m, 1H), 3.60˜3.70(m, 1H),3.84˜3.98(m, 4H), 5.48(dd, 1H), 6.82(d, 1H), 7.19(d, 2H), 7.30˜7.51(m,8H), 7.53˜7.61(m, 1H), 7.87˜7.92(m, 2H), 7.97˜8.02(m, 2H), 8.18˜8.23(m,1H)

Using the compound obtained in the above-described step in a mannersimilar to that of Example 1, potassiumS-4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)-piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoatewas obtained.

MS(m/z):714(MH⁺); IR(KBr)cm⁻¹ :1593, 1576; NMR(DMSO-d₆)δ:1.84˜2.04(m,5H), 2.10˜2.31(m, 4H), 2.44(t, 2H), 2.45˜2.55(br, 4H), 2,92˜3.01(br 4H),3.76(s, 3H), 3.89(s, 3H), 4.24(t, 2H), 5.46(t, 1H), 6.82˜6.96(m, 5H),7.14˜7.38(m, 8H), 7.66(d, 1H), 8.00 (s, 1H), 8.19˜8.24 (m, 1H)

Examples 32-36

Similar to Examples 29-31, the compounds of Examples 32 through 36described below were obtained.

Example 32

Potassium R-4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):714(MH⁺); IR(KBr)cm⁻¹ :1593, 1572; NMR(DMSO-d₆)δ:1.84˜2.04(m,5H), 2.10˜2.31(m, 4H), 2.44(t, 2H), 2.45˜2.55(br, 4H), 2.92˜3.01(br,4H), 3.76(s, 3H), 3.89(s, 3H), 4.24(t, 2H). 5.46(t, 1H), 6.82˜6.96(m,5H), 7.14˜7.38(m, 8H), 7.66(d, 1H), 8.00(s, 1 H), 8.19˜8.24(m, 1H)

Example 33

Potassium R-4-{3-{3-methoxy-4-{1-phenyl-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):700(MH⁺); IR(KBr)cm⁻¹ :1572, 1501; NMR(DMSO-d₆)δ:1.86˜2.25(m,6H), 2.49(t, 2H), 2.50˜2.60(br, 4H), 2.91˜3.01(br, 4H), 3.76(s, 3H),3.90(s, 3H), 4.27(t, 2H), 5.51(t, 1H), 6.82˜6.98(m, 5H), 7.18˜7.48(m,9H), 7.62(d, 1H), 8.02(s, 1H), 8.18˜8.24(m, 1H),

Example 34

Potassium R-4-{3-{3-methoxy-4-{1-phenyl-3-4-(2-ethoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):714(MH⁺); IR(KBr)cm⁻¹ :1595, 1522; NMR(DMSO-d₆)δ:1.83(t, 3H),1.93˜2.26(m, 6H), 2.40˜2.60(m, 6H), 2.95˜3.05(br 4H), 3.90(s, 3H),4.00(q, 2H), 4.28(t, 2H), 5.52(t, 1H), 6.84˜6.96(m, 5H), 7.20˜7.48(m,9H), 7.58˜7.64(m, 1H), 8.03(s, 1H), 8.20˜8.24(m, 1H)

Example 35

Potassium S-4-{3-{3-methoxy-4-{1-phenyl-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):700(MH⁺); IR(KBr)cm⁻¹ :1570, 1501; NMR(DMSO-d₆)δ:1.85˜2.25(m,6H), 2.46(t, 2H), 2.49˜2.59(br, 4H), 2.89˜2.99(br, 4H), 3.76(s, 3H),3.90(s, 3H), 4.24(t, 2H), 5.51(t, 1H), 6.83˜6.97(m, 5H), 7.18˜7.47(m,9H), 7.65(d, 1H), 7.99(s, 1H), 8.19˜8.24(m, 1H)

Example 36

Potassium S-4-{3-{3-methoxy-4-{1-phenyl-3-4-(2-ethoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):714(MH⁺); IR(KBr)cm⁻¹ :1593, 1576; NMR(DMSO-d₆)δ:1.32(t, 3H),1.82˜2.27(m, 6H), 2.46(t, 2H), 2.45˜2.55(br, 4H), 2.93˜3.04(br, 4H),3.90(s, 3H), 3.99(q, 2H), 4.25(t, 2H), 5.51(t, 1H), 6.80˜6.92(m, 4H),6.95(d, 1H), 7.18˜7.49(m, 9H), 7.66(d, 1H), 8.01(s, 1H), 8.20˜8.26(m,1H)

The structures of the compounds obtained in Examples 29 through 36 areshown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________     ##STR8##                                                                     Example No. R1 R2 (absolute configuration)                                                                    R3 M                                          __________________________________________________________________________    29          Me 4-MePh(S)        H  K                                          30          Me 4-MePh(R)        H  K                                          31          Me 4-MePh(S)        MeO                                                                              K                                          32          Me 4-MePh(R)        MeO                                                                              K                                          33          Me Ph(R)            Meo                                                                              K                                          34          Et Ph(R)            MeO                                                                              K                                          35          Me Ph(S)            MeO                                                                              K                                          36          Et Ph(S)            MeO                                                                              K                                          __________________________________________________________________________

Example 37

Potassium 4-{3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

Method A

Step 1:

3-(3-Chloropropoxy)-4-benzyloxybenzoyl chloride, which was preparedusing 4-benzyloxy-3-(3-chloropropoxy)benzoic acid (2.53 g) and oxalylchloride (1 ml), was dissolved in dichloroethane (20 ml). Aluminumchloride (2.63 g) was added to the resultant solution while cooling onice bath, stirred for 5 minutes at room temperature, and then cooledagain on ice bath. 1-(Phenylsulfonyl)indole (1.69 g) in dichloroethane(10 ml) was added dropwise to the resultant mixture and stirred for 2.5hours at room temperature. The reaction mixture was poured into 1N HCland extracted with ethyl acetate. The resultant extract was sequentiallywashed with saturated sodium bicarbonate solution and brine and thendried. The solvent was distilled off. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=3:1), obtaining 0.76 gof 3- 4-hydroxy-3-(3-chloropropoxy)benzoyl!-1-(phenylsulfonyl) indole asa yellow oily substance.

MS(EI, m/z):469, 471(M⁺); IR(KBr)cm⁻¹ :1638, 1593;NMR(CDCl₃)δ:2.35(quint, 2H), 3.76(t, 2H), 4.33(t, 2H), 6.03(br, 1H),7.05(d, 1H), 7.34˜7.63(m, 7H), 7.91˜8.03(m, 4H), 8.18˜8.22(m, 1H)

Step 2:

3- 4-Hydroxy-3-(3-chloropropoxy)benzoyl!-1-(phenylsulfonyl)indole (0.72g) obtained in Step 1 was dissolved in N,N-dimethylformamide (7 ml).α-bromo-p-xylene (0.37 g) and potassium carbonate (0.28 g) were added tothe resultant solution and stirred for 2 hours at room temperature. 2NHCl was added to the reaction mixture, followed by extraction with ethylacetate. The resultant extract was sequentially washed with saturatedsodium bicarbonate solution and brine and then dried. The solvent wasdistilled off. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1), obtaining 0.49 g of 3-4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl!-1-(phenylsulfonyl)indoleas a yellow oily substance.

MS(EI, m/z):573, 575(M⁺); IR(KBr)cm⁻¹ :1638, 1595;NMR(CDCl₃)δ:2.31(quint, 2H), 2.38(s, 3H), 3.79(t, 2H), 4.25(t, 2H),5.21(s, 2H), 7.01(d, 1H), 7.20˜7.62(m, 11H), 7.89˜8.02(m, 4H),8.20˜8.23(m, 1H)

Step 3:

3- 4-(4-Methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl!-1-(phenylsulfonyl)indole (0.44 g) obtained in Step 2 wasdissolved in N,N-dimethylformamide (5 ml). 1-(2-Methoxyphenyl)piperazine(0.20 g), potassium carbonate (0.14 g), and potassium iodide (0.38 g)were added to the resultant solution and the mixture was stirredovernight at 60° C. Water was added to the reaction mixture, followed byextraction with ethyl acetate. The resultant extract was washed withbrine and then dried. The solvent was distilled off. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:3), obtaining 0.29 g of 3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}-1-(phenylsulfonyl)indole(0.29 g) as a light yellow oily substance.

MS(EI, m/z):729(M⁺); IR(KBr)cm⁻¹ :1638, 1593; NMR(CDCl₃)δ: 2.07˜2.13(m,2H), 3.37(s, 3H), 2.60˜2.72(m, 6H), 3.05˜3.13(br, 4H), 3.86(s, 3H),4.20(t, 2H) 5.22(s, 2H) 6.83˜7.02(m, 5H), 7.19˜7.62(m, 11H),7.89˜8.02(m, 4H), 8.20˜8.23(m, 1H)

Step 4:

3-{4-(4-Methylphenylmethoxy)-3-{3- 4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}-1-(phenylsulfonyl)indole (0.26 g)obtained in Step 3 was dissolved in a mixture of methanol (1.5 ml) andtetrahydrofuran (1.5 ml). An aqueous solution of 2N potassium hydroxide(0.5 ml) was added to the resultant solution and stirred overnight atroom temperature. After removing the solvent, water was added to theresidue, followed by extraction with ethyl acetate. The resultantextract was washed with brine and then dried. The solvent was distilledoff. The residue was purified by silica gel column chromatography (ethylacetate), obtaining 0.14 g of 3-{(4-(4-methylphenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}-indole as colorlesscrystals.

mp: 126°-128° C.; MS(EI, m/z):589(M⁺); IR(KBr)cm⁻¹ :1609, 1595;NMR(CDCl₃)δ:1.96˜2.08(m, 2H), 2.28(s, 3H), 2.55˜2.69(m, 6H),3.05˜3.12(br, 4H), 3.83(s, 3H), 4.08(t, 2H), 5.06(s, 2H), 6.83˜7.39(m,13H), 7.44(d, 1H), 7.61(d, 1H), 8.85˜8.38(m, 1H), 10.10(br, 1H)

Step 5:

3-{4-(4-Methylphenylmethoxy)-3-{3- 4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indole (0.12 g) obtained in Step 4 wasdissolved in N,N-dimethylformamide (2 ml). 4-Bromoethylbutyrate (52 mg)and potassium carbonate (33 mg) were added to the resultant solution andstirred for 3 hours at 60° C. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The resultant extract waswashed with brine and then dried. The solvent was distilled off. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:1), obtaining 0.11 g of ethyl4-{3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}-indol-1-yl}butanoateas a light brown oily substance.

MS(m/z):704(MH⁺); IR(neat)cm⁻¹ :1732, 1620, 1595NMR(CDCl₃)δ:1.21(t, 3H),2.02˜2.26(m, 4H) 2.29˜2.36(m, 5H), 2.60˜2.71(m, 6H), 3.033˜3.12(br, 4H),3.86(s, 3H), 4.10(q, 2H), 4.19(t, 2H), 4.25(t, 2H), 5.19(s, 2H),6.84˜7.03(m, 5H)7.18˜7.43(m, 8H), 7.51(d, 1H), 7.59(s, 1H), 8.35˜8.39(m,1H)

The product was subjected to hydrolysis in a manner similar to thatdescribed in Example 1 or 2, obtaining potassium4-{3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate.

MS(m/z):714(MH⁺); IR(KBr)cm⁻¹ :1593, 1576 ; NMR(DMSO-d₆)δ:1.84˜2.02(m,6H), 2.31(s, 3H), 2.45˜2.55(br, 6H), 2.86˜2.95(br, 4H) 3.76(s, 3H),4.12(t, 2H), 4.27(t, 2H) 5.16(s, 2H), 6.78˜6.96(m, 4H), 7.13˜7.31(m,5H), 7.24˜7.45(m, 4H), 7.63˜7.68(m, 1H), 8.02(s, 1H), 8.21˜8.26(m, 1H)

Method B

Step 1:

Ethyl 4- 3-(3,4-dihydroxybenzoyl)indol-1-yl!butanoate (5.70 g) wasdissolved in N,N-dimethylformamide (40 ml). α-bromo-p-xylene (3.72 g)and potassium carbonate (2.57 g) were added to the resultant solutionand stirred for 3 hours at room temperature. The reaction mixture waspoured into 2N HCl and extracted with ethyl acetate. The resultantextract was sequentially washed with saturated sodium bicarbonatesolution and brine, and then dried. The solvent was distilled off. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=3:1), obtaining 2.77 g of ethyl 4-{3-3-hydroxy-4-(4-methylphenylmethoxy)benzoyl!indol-1-yl}butanoate (2.77 g)as light brown crystals.

mp: 125°-127° C.

MS (M/z):472(MH⁺); IR(KBr)cm⁻¹ :1727, 1617, 1597; NMR(CDCl₃)δ:1.22(t,3H), 2.14˜2.34(m, 4H) 2.39(s, 3H), 4.11(q, 2H), 4.25(t, 2H), 5.15(s,2H), 5.78(s, 1H), 7.01(d, 1H), 7.21˜7.43(m, 8H) 7.47(d, 1H), 7.59(s, 1H)8.37˜8.43(m, 1H)

Step 2:

Ethyl 4-{3- 3-hydroxy-4-(4-methylphenylmethoxy)benzoyl!indol-1-yl}butanoate (2.77 g) obtained in Step 1 was dissolvedin N,N-dimethylformamide (30 ml). 1-Bromo-3-chloropropane (1.39 g) andpotassium carbonate (0.97 g) were added to the resultant solution andstirred for 6 hours at 60° C. The reaction mixture was poured into 2NHCl and extracted with ethyl acetate. The resultant extract wassequentially washed with saturated sodium bicarbonate solution and brineand then dried. The solvent was distilled off. The residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=3:1),obtaining 2.67 g of ethyl 4-{3-4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl!indol-1-yl}butanoateas a light yellow oily substance.

MS(m/z):548(MH⁺); IR(neat) cm⁻¹ :1730, 1620, 1597; NMR(CDCl₃)δ:1.21(t,3H), 2.15˜2.35(m, 6H) 2.37(s, 3H), 3.77(t, 2H), 4.10(q, 2H),4.20˜4.29(m, 4H), 5.17(s, 2H), 6.97(d, 1H), 7.17˜7.45(m, 8H), 7.50 (d,1H), 7.59(s, 1H), 8.35˜8.40 (m, 1H)

Step 3:

Ethyl 4-{3-4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl!indol-1-yl}butanoate(2.59 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (30ml). 1-(2-Methoxyphenyl)piperazine (1.36 g), potassium carbonate (0.85g), and potassium iodide (1.02 g) were added to the resultant solutionand stirred overnight at 60° C. The reaction mixture was poured intowater and extracted with ethyl acetate. The resultant extract was washedwith brine and then dried. The solvent was distilled off. The residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=1:2), obtaining 2.47 g of ethyl4-{3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoateas a colorless oily substance.

The product was subjected to hydrolysis in a manner similar to thatdescribed in Example 1 or 2, obtaining potassium4-{3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate.

Examples 38-44

Similar to Example 37, the compounds of Examples 38 through 48 describedbelow were prepared.

Example 38

Potassium 4-{3-{4-benzyloxy-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):700 (MH⁺); IR(KBr)cm⁻¹ :1595, 1576; NMR(DMSO-d₆)δ1.86˜2.04 (m,4H), 2.10˜2.18 (m, 2H), 2.45˜2.55 (m, 6H), 2.86˜2.96 (br, 4H) 3.76 (s,3H), 4.13 (t, 2H), 4.29 (t, 2H) 5.22 (s, 2H), 6.77˜6.95 (m, 4H),7.15˜7.52 (m, 10H), 7.60˜7.65 (m, 1H), 8.04 (s, 1H), 8.22˜8.26 (m, 1H)

Example 39

4-{3-{4-Benzyloxy-3-{1-(4-methylphenyl)-3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1- yl}butanoicacid

MS(m/z):752 (MH⁺); IR(KBr)cm⁻¹ :1595, 1572; NMR(CDCl₃)δ:2.08˜2.45 (m,8H), 2.75˜2.85 (m, 1H), 3.00˜3.17 (m, 6H), 3.20˜3.36 (br, 4H), 3.86 (s,3H), 4.31˜4.42 (m, 1H), 4.52˜4.64 (m, 1H), 5.21 (s, 2H), 5.52˜5.60 (m,2H), 6.85˜7.07 (m, 7H), 7.20˜7.48 (m, 12H), 7.73 (s, 1H) 8.45˜8.52 (m,1H)

Example 40

Sodium 4-{3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-propoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):726 (MH⁺); IR(KBr)cm⁻¹ :1595, 1576; NMR(DMSO-d₆)δ:1.02 (t, 3H),1.67˜2.00 (m, 8H), 2.31 (s, 3H), 2.45˜2.55 (br, 6H), 2.90˜3.00 (br, 4H),3.90 (t, 2H), 4.13 (t, 2H), 4.26 (t, 2H), 5.15 (s, 2H), 6.76˜6.92 (m,4H), 7.12˜7.31 (m, 5H), 7.35˜7.47 (m, 4H), 7.69 (dd, 1H), 8.00 (s, 1H),8.20˜8.25 (m, 1H)

Example 41

Potassium 4-{3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-isopropoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):742 (MH⁺); IR(KBr)cm⁻¹ :1593, 1574; NMR(DMSO-d ₆)δ:1.26 (d, 6H),1.89˜2.06 (m, 4H), 1.99˜2.23 (m, 2H), 2.31 (s, 3H), 2.48˜2.69 (m, 6H),2.96˜3.03 (m, 4H), 4.11˜4.21 (m, 2H), 4.27˜4.38 (m, 2H), 4.51˜4.62 (m,1H), 5.17 (s, 2H), 6.83˜6.88 (m, 5H), 7.15˜7.41 (m, 8H), 7.63 (d, 1H),8.04 (s, 1H), 8.24 (d, 1H)

Example 42

Potassium 4-{3-{4-(4-fluorophenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):718 (MH⁺); IR(KBr)cm⁻¹ :1595, 1575; NMR(DMSO-d₆)δ:1.85˜2.20 (m,6H), 2.40˜2.55 (m, 6H), 2.85˜2.96 (br, 4H), 3.76 (s, 3H), 4.13 (t, 2H),4.29 (t, 2H), 5.20 (s, 2H), 6.77˜6.95 (m, 4H), 7.15˜7.33 (m, 5H),7.38˜7.45 (m, 2H), 7.50˜7.65 (m, 3H), 8.03 (s, 1H), 8.20˜8.26 (m, 1H)

Example 43

Sodium 4-{3-{4-(4-ethylphenylmethoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):711 (MH⁺); IR(KBr)cm⁻¹ :1593, 1572; NMR(DMSO-d₆)δ:1.17 (t, 3H),1.79˜1.98 (m, 6H), 2.45˜2.55 (br, 6H), 2.61 (q, 2H), 2.87˜2.97 (br, 4H),3.76 (s, 3H), 4.13 (t, 2H), 4.27 (t, 2 H), 5.17 (s, 2H), 6.76˜6.96 (m,4H), 7.15˜7.30 (m, 5H), 7.38˜7.46 (m, 4H), 7.66˜7.72 (m, 1H), 8.01 (s,1H), 8.20˜8.25 (m, 1H)

Example 44

Potassium 4-{3-{4-(4-phenylbutoxy)-3-{3-4-(2-methoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl}butanoate

MS(m/z):742 (MH⁺); IR(KBr)cm⁻¹ :1595, 1573; NMR(DMSO-d₆)δ:1.72˜1.99 (m,10H), 2.42˜2.53 (m, 6H), 2.68 (t, 2H), 2.86˜2.95 (br, 4 H), 3.76 (s,3H), 4.04˜4.13 (m, 4H), 4.27 (t, 2H), 6.78˜6.96 (m, 4H), 7.07 (d, 1H),7.13˜7.31 (m, 7H), 7.37 (d, 1H), 7.45 (dd, 1H), 7.67 (dd, 1H), 8.00 (s,1H), 8.20˜8.25 (m, 1H)

Example 45

Potassium 4-{3-{4-(4-methylphenylmethoxy)-3-{3-4-(2-ethoxyphenyl)piperazin-1-yl!propoxy}benzoyl}indol-1-yl }butanoate

MS(m/z):728 (MH⁺); IR(KBr)cm⁻¹ :1593, 1575; NMR(DMSO-d₆)δ:1.33 (t, 3H),1.92˜1.99 (m, 4H), 2.05˜2.09 (m, 2H), 2.31 (s, 3H) 2.49˜2.51 (m, 6H),2.90˜2.98 (m, 4H), 4.00 (q, 2H), 4.12 (t, 2H), 4.28 (t, 2H), 5.16 (s,2H), 6.77˜6.90 (m, 4H), 7.14˜7.31 (m, 5H), 7.36˜7.44 (m, 4H), 7.64 (d,1H), 8.02 (s, 1H), 8.23 (dd, 1H)

Example 46

Potassium 4-{3-{3-{4-4-(2-methoxyphenyl)piperazin-1-yl!butoxy}-4-(4-methylphenylmethoxy)benzoyl}indol-1-yl}butanoate

MS(m/z):728 (MH⁺); IR(KBr)cm⁻¹ :1593, 1576; NMR(DMSO-d₆)δ:1.59˜1.64 (m,2H), 1.75˜1.82 (m, 2H), 1.89˜1.96 (m, 4H), 2.30 (s, 3H), 2.37 (t, 2H),2.47˜2.53 (m, 4H), 2.88˜2.94 (m 4H), 3.76 (s, 3H), 4.10 (t, 2H),4.24˜4.28 (m, 2H) 5.15 (s, 2H), 6.82˜6.93 (m, 4H) 7.15˜7.30 (m, 5H),7.36˜7.4 (m, 4H), 7.67 (d, 1H), 8.01 (s, 1H) 8.22 (dd, 1H)

Example 47

Potassium 4-{3-{3-{4- 4-(2-ethoxyphenyl)piperazin-1-yl!butoxy}-4-(4-methylphenylmethoxy)benzoyl}indol-1-yl}butanoate

MS(m/z):742(MH⁺); IR(KBr)cm⁻¹ :1593, 1575; NMR(DMSO-d₆)δ:1.32˜2.01 (t, 3H), 1.57˜1.69 (m, 2H), 1.64˜2.12 (m, 6 H), 2.18 (t, 2H), 2.29 (s, 3 H),2.38 (t, 2 H), 2.48˜2.50 (m, 4H), 2.87˜2.98 (m, 4 H), 3.99 (q, 2 H),4.10 (t, 2 H), 4.29 (t,2H), 5.16 (s, 2 H),6.80˜6.89 (m, 4 H), 7.15˜7.42(m, 9H), 7.63 (d, 1 H), 8.03 (s, 1 H), 8.23 (dd, 1 H),

Example 48

Potassium 4-{3-{3-{2-4-(2-methoxyphenyl)piperazin-1-yl!ethoxy}-4-(4-methylphenylmethoxy)benzoyl}indol-1-yl}butanoate

MS(m/z):700(MH+); IR(KBr)cm⁻¹ :1593, 1574; NMR(DMSO-d₆)δ:1.93˜2.01 (m, 2H), 2.02˜2.10 (m, 2 H), 2.30 (s, 3 H), 2.62˜2.70 (m, 2 H), 2.74˜2.81 (m,2 H), 2.86˜2.94 (m, 4 H), 3.76(s, 3 H), 4.21 (t, 2 H), 4.29 (t, 2 H),5.16 (s,2H), 6.82˜6.93 (m, 4 H) 7.1 6˜7.32 (m, 5 H), 7.37˜7.44 (m, 4 H),7.66 (d, 1 H), 8.04 (s, 1 H), 8.22 (dd, 1 H),

The structures of the compounds obtained in Examples 37 through 48 areshown in Table 3.

                                      TABLE 3                                     __________________________________________________________________________     ##STR9##                                                                     Example No.                                                                            R1   R2     R3        n    M                                         __________________________________________________________________________    37       Me   H      4-MePhCH.sub.2 O                                                                        2    K                                         38       Me   H      PhCH.sub.2 O                                                                            2    K                                         39       Me   4-MePh PhCH.sub.2 O                                                                            2    H                                         40       n-Pr H      4-MePhCH.sub.2 O                                                                        2    Na                                        41       i-Pr H      4-MePhCH.sub.2 O                                                                        2    K                                         42       Me   H      4-FPhCH.sub.2 O                                                                         2    K                                         43       Me   H      4-EtPhCH.sub.2 O                                                                        2    Na                                        44       Me   H      4-Ph(CH.sub.2).sub.4 O                                                                  2    K                                         45       Et   H      4-MePhCH.sub.2 O                                                                        2    K                                         46       Me   H      4-MePhCH.sub.2 O                                                                        3    K                                         47       Et   H      4-MePhCH.sub.2 O                                                                        3    K                                         48       Me   H      4-MePhCH.sub.2 O                                                                        1    K                                         __________________________________________________________________________

Test Example 1 α₁ -Adrenoceptor Blocking Action

Male albino rabbits were sacrificed by exsanguination, and the prostateand urethra were isolated. After removal of fat and connective tissues,tranverse smooth muscle strips were prepared from prostate and proximalurethra. Each segmental strip was suspended in an organ bath at 37° C.in a Krebs-Henseleit solution which had been bubbled with 95% O₂ and 5%CO₂. The isometric contraction under a resting tension of 1 g wasrecorded with a force-displacement transducer(TB-651T, Nihon Koden) on arecoder(RECTI HORIZ 8K, Nihon Sanei).

After an equilibration of tissues at least 60 minutes, contractions wereelicited by repeated dose of phenylephrine until constant contractionresponses were obtained. Subsequently, the dose-response curves wereobtained by increasing concentrations of phenylephrine(10⁻⁷ -×10⁻⁴ M).After the resting period for 60 minutes, tissues were incubated withtest drugs for 30 minutes and dose-response curves were constructed asdescribed above.

In all cases, 10⁻⁵ M propranolol(β-adrenoceptor antagonist) wasadministered 10 minutes before the contraction by phenylephrine.

The composition of the Krebs-Henseleit solution was as follows(mM): NaCl118.4, KCl 4.7, MgSO₄ 1.2, CaCl₂ 2.5, NaHCO₃ 25.0, glucose 11.1, KH₂ PO₄1.2.

The potency of each test drug was expressed as the pA₂ value(negativelogarithm of the antagonist dissociation constant). The results areshown in Table 4.

                  TABLE 4                                                         ______________________________________                                        α.sub.1 -Adrenoceptor blocking action                                   Example         Urethra Prostate                                              No.             (pA.sub.2)                                                                            (pA.sub.2)                                            ______________________________________                                         1              6.42    7.06                                                   3              6.94    7.12                                                   5              5.96    6.85                                                  14              6.41    7.14                                                  15              6.60    7.30                                                  16              6.81    7.07                                                  20              6.16    6.25                                                  24              6.20    7.00                                                  28              6.78    6.99                                                  35              7.19    7.56                                                  37              6.92    7.72                                                  38              7.44    7.78                                                  42              6.40    7.15                                                  45              7.25    7.46                                                  ______________________________________                                    

Test Example 2 Testosterone 5α-Reductase Inhibitory Action

Male Wistar rats (age: 9-10 weeks old) were anesthetized with ethylether and ventral prostates were dissected. The isolated prostates wereweighed and homogenized with ultradisperser(Yamato, Japan) andteflon-glass homogenizer in 3 tissue volumes of 50 mM Tris-HCl buffer(pH7.2) containing 0.25M sucrose and 1 mM dithiothreitol. The homogenateswere filtered with gauze and centrifuged at 3,000 rpm for 10 minutes at4° C. The pellets were resuspended in same buffer as described above andthe resultant suspension was used as the nuclear fraction.

Testosterone 5α-reductase activity was carried out described as follows.The reaction mixture contained 0.ml of nuclear fraction 0.1 ml of 5 mMNADPH, 0.01 ml of test drug dissolved in dimethylsulfoxide and 0.78ml ofTris-HCl buffer(pH 7.0). The reaction was started by addition of 0.01 mlof 150 μM 4-¹⁴ C!-testosterone and incubated for 60 minutes at 37° C.After incubation, reaction was stopped by adding 4 ml of ethyl acetate.3 ml of ethyl acetate was evaporated under nitrogen to dryness anddissolved in 40 μl of ethyl acetate. 10 μl of ethyl acetate was appliedto silica gel thin layer plate(HF₂₅₄, Merck) and the plate was developedin ethyl acetate and cyclohexane(1:1). The plate was subjected toautoradiography and the radioactivity profiles were determined byscraping the spots of testosterone, dihydrotestosterone and othermetabolites and counting in a scintillation counter. Testosterone 5a-reductase activity was calculated for the total radioactivity andradioactivities of dihydrotestosterone and other metabolites. Theinhibitory activity of test drug was expressed as IC₅₀ (nM). The resultsare shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        Testosterone 5α-reductase inhibitory action                                    Example No.                                                                           IC.sub.50 (nM)                                                 ______________________________________                                                1      3.7                                                                    8      0.26                                                                  11      3.1                                                                   13      1.4                                                                   15      7.9                                                                   22      3.7                                                                   26      5.0                                                                   35      6.8                                                                   37      3.5                                                                   45      1.5                                                                   46      1.5                                                            ______________________________________                                    

From Tables 5 and 6, it is apparent that the compound (1) of the presentinvention or a salt thereof has excellent α₁ -adrenergic receptorblocking action and testosterone 5α-reductase inhibitory action.

Test Example 3

Toxicity Test:

Groups of ICR mice (Charles River, age: 4-5 weeks old), each groupconsisting of 10 mice, were used. A compound of each Example wassuspended in 10% gum arabic. The suspension was intraperitoneallyadministered to each mouse at a dose of 100 mg/kg. The mice wereobserved over 7 days. No casualty took place at this dosage.

Preparation Example 1

The compound (20 g) of Example 1, lactose (315 g), corn starch (125 g),and crystalline cellulose (25 g) were mixed uniformly. An aqueous 7.5%solution (200 ml) of hydroxypropylcellulose was added thereto. Theresultant mixture was granulated with an extruding granulator equippedwith a screen having a mesh of 0.5 mm diameter. The thus-preparedgranules were immediately rounded with a marumerizer and then dried,obtaining a granular agent.

Preparation Example 2

Granules prepared in Preparation Example 1 were coated with a filmcoating liquid (1.9 kg) having the following composition using afluidized granulator, thereby obtaining an enteric granular agent.

Composition of coating liquid: hydroxypropyl-methylcellulose phthalate(5.0%), stearic acid (0.25%), methylene chloride (50.0%), ethanol(44.75%)

Preparation Example 3

The compound (20 g) of Example 15, lactose (100 g), corn starch (36 g),crystalline cellulose (30 g), carboxymethylcellulose calcium (10 g), andmagnesium stearate (4 g) were mixed uniformly. The resultant mixture wasformed into tablets, 200 mg each, using a single-punch tableting machinewhich has a pestle of 7.5 mm in diameter.

Preparation Example 4

Tablets prepared in Preparation Example 3 were spray-coated with acoating liquid having the following composition, thereby obtainingenteric film-coated tablets, each coated with 10 mg coating.

Composition of coating liquid: hydroxypropyl-methylcellulose phthalate(8.0%), maibaset (0.4%), methylene chloride (50.0%), bleached beeswax(0.1%), and isopropanol (41.5%)

Preparation Example 5

The compound (200 g) of Example 22, polysorbate 80 (20 g), and mediumchain fatty acid triglyceride (1780 g) were mixed and dissolvedcompletely. Subsequently, the resultant solution was formed into a softcapsulated agent, each capsule containing 200 mg of the solution, by arotary method using a soft capsulating liquid, which is composed ofgelatin (100 parts), thick glycerin (30 parts), ethyl paraben (0.4parts), and propyl paraben (0.2 parts).

Preparation Example

    ______________________________________                                        Compound of Example 23  100 mg                                                Sodium acetate           2 mg                                                 Acetic acid (for preparation to pH 5.8)                                                               Suitable amount                                       Distilled water         Balance                                               Total                   10 ml/vial                                            ______________________________________                                    

The above ingredients were processed by a routine method to obtain aninjection agent.

Industrial Applicability

The compound (1) of the present invention has both α₁ -adrenergicreceptor blocking action and testosterone 5α-reductase inhibitoryaction, and thus is useful as a remedy and/or a preventive for diseasescaused by overproduction of dihydrotestosterone, e.g., prostatichypertrophy or accompanying urination disorder, male pattern alopecia,and acne.

We claim:
 1. An indole derivative represented by the following formula(1) or a salt thereof: ##STR10## wherein R¹ represents lower alkyl; R²represents hydrogen or phenyl which may be substituted by at least onelower alkyl, lower alkoxy or a halogen atom; R³ represents hydrogen,lower alkyl, lower alkoxy, or phenylalkyloxy which may be substituted byhalogen or lower alkyl; R⁴ represents hydrogen, lower alkyl or loweralkoxy; R⁵ represents hydrogen or lower alkyl; and n represents aninteger of 1 to
 5. 2. An indole derivative or a salt thereof as definedin claim 1, wherein the lower alkyl is C1-C6 linear or branched alkyl;and the lower alkoxy is C1-C6 linear or branched alkoxy.
 3. An indolederivative or a salt thereof as defined in claim 1, wherein R² is phenylwhich may be substituted by at least one lower alkyl, lower alkoxy, or ahalogen atom.
 4. An indole derivative or a salt thereof as defined inclaim 3, wherein the absolute configuration is an S-configuration.
 5. Atestosterone 5α-reductase inhibitor comprising as an effectiveingredient an indole derivative or a salt thereof as defined in claim 1.6. An a₁ -adrenergic receptor blocker comprising as an effectiveingredient an indole derivative or a salt thereof as defined in claim 1.7. A therapeutic agent for prostatic hypertrophy as well as forurination disorder, alopecia, and acne which accompany prostatichypertrophy, comprising as an effective ingredient an indole derivativeor a salt thereof as defined in claim
 1. 8. A pharmaceutical compositioncomprising an indole derivative or a salt thereof as defined in claim 1and a carrier for pharmaceuticals.
 9. A composition as defined in claim8, which is used for the treatment of prostatic hypertrophy as well asurination disorder, alopecia, and acne which accompany prostatichypertrophy.
 10. A method for the treatment of prostatic hypertrophy aswell as urination disorder, alopecia, and acne which accompany prostatichypertrophy, characterized by administering an effective amount of anindole derivative or a salt thereof as described in claim 1.